title: Panobinostat synergistically enhances the cytotoxic effects of cisplatin, doxorubicin or etoposide on high-risk neuroblastoma cells.
abstract: High-risk neuroblastoma remains a therapeutic challenge with a long-term survival rate of less than 40%. Therefore, new agents are urgently needed to overcome chemotherapy resistance so as to improve the treatment outcome of this deadly disease. Histone deacetylase (HDAC) inhibitors (HDACIs) represent a novel class of anticancer drugs. Recent studies demonstrated that HDACIs can down-regulate the CHK1 pathway by which cancer cells can develop resistance to conventional chemotherapy drugs. This prompted our hypothesis that combining HDACIs with DNA damaging chemotherapeutic drugs for treating neuroblastoma would result in enhanced anti-tumor activities of these drugs. Treatment of high-risk neuroblastoma cell lines with a novel pan-HDACI, panobinostat (LBH589), resulted in dose-dependent growth arrest and apoptosis in 4 high-risk neuroblastoma cell lines. Further, the combination of panobinostat with cisplatin, doxorubicin, or etoposide resulted in highly synergistic antitumor interactions in the high-risk neuroblastoma cell lines, independent of the sequence of drug administration. This was accompanied by cooperative induction of apoptosis. Furthermore, panobinostat treatment resulted in substantial down-regulation of CHK1 and its downstream pathway and abrogation of the G2 cell cycle checkpoint. Synergistic antitumor interactions were also observed when the DNA damaging agents were combined with a CHK1-specific inhibitor, LY2603618. Contrary to panobinostat treatment, LY2603618 treatments neither resulted in abrogation of the G2 cell cycle checkpoint nor enhanced cisplatin, doxorubicin, or etoposide-induced apoptosis in the high-risk neuroblastoma cells. Surprisingly, LY2603618 treatments caused substantial down-regulation of total CDK1. Despite this discrepancy between panobinostat and LY2603618, our results indicate that suppression of the CHK1 pathway by panobinostat is at least partially responsible for the synergistic antitumor interactions between panobinostat and the DNA damaging agents in high-risk neuroblastoma cells. The results of this study provide a rationale for clinical evaluation of the combination of panobinostat and cisplatin, doxorubicin, or etoposide for treating children with high-risk neuroblastoma.
authors.affiliation: Department of Pediatrics, Wayne State University School of Medicine, Detroit, Michigan, United States of America ; College of Life Science, Jilin University, Changchun, China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.forename: Holly
authors.initials: H
authors.lastname: Edwards
authors.forename: J Timothy
authors.initials: JT
authors.lastname: Caldwell
authors.forename: Steven A
authors.initials: SA
authors.lastname: Buck
authors.forename: William Y
authors.initials: WY
authors.lastname: Qing
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Taub
authors.forename: Yubin
authors.initials: Y
authors.lastname: Ge
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Wang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000071877:Checkpoint Kinase 1; D002945:Cisplatin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D009447:Neuroblastoma / Q000188:drug therapy*; D000077767:Panobinostat; D010671:Phenylurea Compounds; D011494:Protein Kinases / Q000378:metabolism; D011719:Pyrazines
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; C582547:LY2603618; D010671:Phenylurea Compounds; D011719:Pyrazines; D005047:Etoposide; D004317:Doxorubicin; D000077767:Panobinostat; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D002945:Cisplatin